The Differential Effects of Two Critical Osteoclastogenesis Stimulating Factors on Bone Biomechanics

Many skeletal diseases, such as osteoporosis and malignant bone metastases, are generally osteolytic and associated with increased bone resorption and decreased bone strength. Within a complex cytokine environment, the proteins RANKL and M-CSF are critical for osteoclast differentiation and activation, and thus fundamental effectors of osteolytic disorders. Previous studies showed that M-CSF stimulates the proliferation and early differentiation of osteoclast progenitors to osteoclast lineage, while RANKL targets the later stages of fusion and activation, and stimulates the formation of functional active osteoclasts. However, impacts of artificially elevated levels of these proteins on the skeleton system have not been fully characterized. In this project, we amplified the circulating levels of RANKL and M-CSF by injections or continuous administrations and examined the effects on bone volume and quality. We hypothesized that while M-CSF and RANKL can both stimulate osteoclastogenesis, the differences in activation stages targeted by these two cytokines would result in distinct responses on bone biomechanics. RANKL would directly stimulate osteoclast activity and increase bone resorption, while M-CSF would act anabolically through coupling between osteoblast development and the promoted osteoclastogenesis at the early stage, and promote bone formation indirectly. Data obtained in this project demonstrated that in vivo administration of RANKL and M-CSF induced general opposing effects on bone volume, architecture, mineralization and strength. RANKL directly stimulated bone resorption and reduceed bone biomechanical properties. The destructive skeleton induced by RANKL could serve as a novel animal model that exhibits a series of skeletal complications similar to those observed in osteolytic skeletal diseases, such as osteoporosis. Alternately, administrations of M-CSF markedly stimulated trabecular bone formation and had less of an influence on cortical bone. These changes demonstrated the potential of M-CSF as an anabolic agent for osteoporosis. This project has further examined the in vivo characteristics and functional effects of RANKL and M-CSF on the skeleton system. Findings in this project, such as the creation of RANKL induced bone loss model and characterization of the anabolic potential of M-CSF on the skeleton, could provide useful information and tools for further explorations on human skeletal diseases